Pediatr Transplantation 2014: 18: 221–229

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric Transplantation DOI: 10.1111/petr.12213

Unrelated donor cord blood transplantation for non-malignant disorders in children and adolescents Park M, Lee YH, Kang H-R, Lee JW, Kang HJ, Park KD, Shin HY, Ahn HS, Baek HJ, Kook H, Hwang TJ, Lee JW, Chung N-G, Cho B, Kim H-K, Lee SH, Yoo KH, Sung KW, Koo HH, Koh KN, Im HJ, Seo JJ, Park JE, Lim YJ, Lyu CJ, Lee JM, Hah JO on behalf of the Korean Cord Blood Transplantation Working Party. Unrelated donor cord blood transplantation for non-malignant disorders in children and adolescents. Abstract: This study analyzes the data reported to the Korean Cord Blood Registry between 1994 and 2008, involving children and adolescents with non-malignant diseases. Sixty-five patients were evaluated in this study: SAA (n = 24), iBMFS, (n = 16), and primary immune deficiency/inherited metabolic disorder (n = 25). The CI of neutrophil recovery was 73.3% on day 42. By day 100, the CI of acute grade II–IV graft-versus-host disease was 32.3%. At a median followup of 71 months, five-yr OS was 50.7%. The survival rate (37.5%) and CI of neutrophil engraftment (37.5%) were lowest in patients with iBMFS. Deaths were mainly due to infection, pulmonary complications, and hemorrhage. In a multivariate analysis, the presence of >3.91 9 105/kg of infused CD34 + cells was the only factor consistently identified as significantly associated with neutrophil engraftment (p = 0.04) and OS (p = 0.03). UCBT using optimal cell doses appears to be a feasible therapy for non-malignant diseases in children and adolescents for whom there is no appropriate HLAmatched related donor. Strategies to reduce transplant-related toxicities would improve the outcomes of UCBT in non-malignant diseases.

Meerim Park1, Young Ho Lee2, Hae-Ryong Kang2, Ji Won Lee3, Hyoung Jin Kang3, Kyung Duk Park3, Hee Young Shin3, Hyo Seop Ahn3, Hee Jo Baek4, Hoon Kook4, Tai Ju Hwang4, Jae Wook Lee5, Nack-Gyun Chung5, Bin Cho5, Hack-Ki Kim5, Soo Hyun Lee6, Keon Hee Yoo6, Ki Woong Sung6, Hong Hoe Koo6, Kyung Nam Koh7, Ho Joon Im7, Jong Jin Seo7, Jun Eun Park8, Yeon Jung Lim9, Chuhl Joo Lyu10, Jae Min Lee11, and Jeong Ok Hah11 on behalf of the Korean Cord Blood Transplantation Working Party 1

Department of Pediatrics, Chungbuk National University College of Medicine, Cheongju, South Korea, 2Department of Pediatrics, Hanyang University Medical Center, Hanyang University College of Medicine, Seoul, South Korea, 3 Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea, 4Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea, 5Department of Pediatrics, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea, 6 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, 7Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, South Korea, 8 Department of Pediatrics, Ajou University School of Medicine, Suwon, South Korea, 9Department of Pediatrics, Chungnam National University College of Medicine, Daejon, South Korea, 10Department of Pediatrics, Yonsei University, College of Medicine, Seoul, South Korea, 11Department of Pediatrics, Yeungnam University College of Medicine, Daegu, South Korea Key words: unrelated cord blood transplantation – non-malignant disease – children – adolescents Young Ho Lee, Department of Pediatrics, Hanyang University Medical Center, Hanyang University College of Medicine, Wangsimni-ro, 222, Seongdong-gu, Seoul, Korea Tel.: 82 2 2290 8383 Fax: 82 2 2297 2380 E-mail: [email protected]

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Park et al. [Correction added on 3rd January 2014, after first online publication: Jae Min Lee has been added to the author’s list.] Accepted for publication 22 November 2013

A wide spectrum of non-malignant diseases, including SAA, iBMFS, PIDs, and IMDs, can be treated successfully by allogeneic HSCT. In each of these diseases, donor-derived cells can correct the underlying defect, either by direct repopulation of the hematopoietic and immune systems or by indirect delivery of the missing enzymes or other critical building blocks across cell membranes (1). The advantages of unrelated CB donors such as faster availability, tolerance to one or two HLA mismatches, and low incidence of acute GVHD make UCBT an attractive option for some patients with non-malignant diseases (2). In addition, hematopoietic progenitor cells derived from related or unrelated CB units are known to be at least as effective as those derived from BM or growth factor-mobilized PB (3–5). However, only a limited number of patients with non-malignant diseases have undergone UCBT, and the follow-up periods have been short (4, 6). Overall experience on UCBT is still limited, and additional study is therefore required to determine the benefits of these alternative therapies (7). Here, we report an analysis of the outcomes of UCBT in children and adolescents with non-malignant disorders in Korea. Materials and methods Data collection and patient selection This retrospective study was based on data reported to the Korean Cord Blood Registry from 18 transplant centers. All CB units in the registry were obtained from Korean cord blood banks. More than 400 transplants have been registered. All registered patients who received UCBT for non-malignant diseases were included in this study. In December 2011, 65 of 381 patients were evaluated for this study. The study was approved by the Institutional Review Board of Hanyang University Medical Center, and informed consent was obtained from patients and/or guardians before UCBT.

Definitions OS was defined as the time between the date of transplantation and the date of death from any cause, or, for survivors, the date of the last follow-up. TRM was defined as any death not due to progression or persistence of the underlying disease. Other end-points include the incidence of neutrophil recovery, defined as the first of three consecutive days with a neutrophil count of at least 0.5 9 109/L. GF was defined as the absence of hematopoietic recovery by day 42, second transplantation or autologous reconstitution. RIC was defined according to the published criteria (8). The choice of preparative regimen reflected institutional preferences. Acute GVHD was diagnosed and graded according to the international criteria (9). Chronic GVHD was evaluated only in patients who survived more than 100 days after HSCT with sustained donor engraftment, using previously published criteria (10). CMV reactivation was defined as either CMV antigenemia (≥1 CMV pp65positive cells/50 000) or DNAemia (≥500 copies by quantitative [PCR]). CMV disease was defined as end-organ disease, such as pneumonia, gastrointestinal disease, hepatitis, etc., with a documented CMV etiology (11). EBV reactivation was defined as any EBV PCR load above 1000 copies of EBV DNA per 105 cells. EBV-PTLD was defined as biopsy-proven post-transplantation lymphoma or reactivation along with computerized tomography nodal or soft-tissue abnormalities consistent with PTLD (12). Typing of HLA antigens was performed using a DNA-based methodology: A high-resolution technique was used for class II antigens, and low-resolution typing was used for HLA-A and HLA-B loci. Chimerism was evaluated in the first three months after UCBT as reported by the centers, or after, that in cases of secondary GF. Full donor chimerism was defined as the presence of more than 95% of donor cells, mixed chimerism when the proportion of donor cells was >5% and ≤95%, while autologous recovery if ≤5% of donor cells were present. During the study period, fluorescent in situ hybridization of sex chromosome (XY-FISH) and PCR-based analysis of polymorphic DNA sequences such as STR were the most widely used techniques for chimerism analyses.

Statistical analysis The CIs of neutrophil recovery and GVHD were calculated by Gray’s method. For neutrophil engraftment, the

Abbreviations: BM, bone marrow; BMT, bone marrow transplantation; CB, cord blood; CI, cumulative incidence; EBV, Epstein–Barr virus; EBV-PTLD, EBV-related post-transplantation lymphoproliferative disease; FHLH, familial hemophagocytic lymphohistiocytosis; GF, graft failure; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; iBMFS, inherited bone marrow failure syndrome; IMDs, inherited metabolic disorders; LAD, leukocyte adhesion deficiency; MAC, myeloablative conditioning; OS, overall survival; PB, peripheral blood; PCR, polymerase chain reaction; PIDs, primary immune deficiency diseases; RIC, reduced-intensity conditioning; SAA, severe aplastic anemia; STR, short tandem repeats; TBI, total body irradiation; TRM, transplantation-related mortality; UCBT, unrelated CB transplantation.

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UCBT for non-malignant disorders competing risks were autologous recovery, infusion of a backup graft, or death. GF and death were the competing events for GVHD. To identify prognostic factors influencing neutrophil recovery and OS after UCBT in each disease group, univariate proportional hazard regression models were used. Multivariate analysis was used to analyze the prognostic factors influencing neutrophil recovery and OS after UCBT in the study group as a whole. The following variables were analyzed: age, HLA compatibility, ABO match, time between diagnosis and UCBT, conditioning regimen, use of methotrexate as GVHD prophylaxis, number of total nucleated cells, and number of infused CD34 + cells. Factors significant at the 0.3 level on univariate analysis were considered for multivariate analysis using backward elimination. Survival was calculated by the Kaplan–Meier method. Two-sided p values of

Unrelated donor cord blood transplantation for non-malignant disorders in children and adolescents.

This study analyzes the data reported to the Korean Cord Blood Registry between 1994 and 2008, involving children and adolescents with non-malignant d...
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